The basic objective of this proposal is to develop and animal model with altered capacity to repair DAN damage that can eventually be used to test the somatic mutation theory of aging. To accomplish this objective, I propose to characterize the DNA polymerase beta knockout mouse for the following reasons. First, mice with reduced levels of DNA polymerase beta would be expected to have a reduced ability to repair most types of endogenous DNA damage because DAN polymerase beta (beta-pol) plays a central role in base excision repair. Second, a null mutation in one of the genetic components of the base excision repair pathway seems to be the most likely way of altering base excision repair at the present time. Third preliminary data from Dr. Wilson~s laboratory suggests that embryonic cells from heterozygous beta-pol-+ mice have reduced levels of DNA polymerase beta and reduced ability to repair DAN damage. The two specific aims of the research described in this proposal are as follows: 1. To characterize the expression of DNA polymerase beta in heterozygous beta-pol-+ knockout mice. The expression of beta-pol (mRNA and protein levels) and beta-pol enzymatic activity will be measured in various tissues (liver, heart, brain, muscle, spleen, intestine, and skin of young/adult (3-4 month old) heterozygous beta-pol-+ mice and compared to normal, non-transgenic animals. 2. To measure the DNA repair capacity in heterozygous beta-pol-+ knockout mice. The DNA repair capacity of various tissues (liver, heart, brain, muscle, spleen, intestine, and skin) of beta-pol-+ mice will be measured in vitro using an assay for base excision repair of a G:U mismatch as well as in vivo by measuring repair of DNA damage/mutations induced by X-ray radiation and alkylating agents. The data generated from these two specific aims will provide me with preliminary data that will be used in future grant applications to use the heterozygous beta-pol-+ mouse model to test the following hypothesis: alterations in DNA repair capacity in cells/tissues that gives rise to an alteration in the accumulation of DNA damage/mutations with age will be associated with changes in the longevity of the organism.